After two years unsuccessfully trying to make an NFL roster (featuring brief stints with the Miami Dolphins and the Green Bay Packers), Heupel became a coach.

[5] His mother, Cindy, was a high school principal, and his father, Ken, was a head football coach at Northern State University.

[7] In the second half of the first game of his sophomore season in 1994, he became the Golden Eagles' quarterback in a scaled-down version of the run and shoot offense.

He got recruiting inquiries from major college football programs at the universities of Houston, Minnesota, Wisconsin and Wyoming, but "it seemed I was always the second or third guy on their list," according to Heupel.

[8] He redshirted in 1996 and saw action in four games as a freshman in 1997, but he suffered an ACL injury during spring practice in 1998,[9] pushing him down the team's depth chart.

He transferred to Snow College in Ephraim, Utah, where he beat out Fred Salanoa as the team's starting quarterback.

[14][15][16] Heupel led the Sooners to an undefeated season and a national championship with a 13–2 victory over Florida State in the 2001 Orange Bowl.

[20] Compromised by shoulder tendinitis of his throwing arm, he was relegated to fourth string for the entire preseason and failed to make the team.

[27][28] On December 13, 2010, Bob Stoops named Heupel and Jay Norvell as co-offensive coordinators at Oklahoma, replacing Kevin Wilson, who had accepted the head coaching job at Indiana.

[32][33] Heupel was named head coach of the UCF Knights on December 5, 2017, replacing the departing Scott Frost.

[34] In the 2018 season, Heupel led UCF to a 12–1 record and an American Athletic Conference Football Championship Game victory.

[42] In his first season with Tennessee, Heupel led the Volunteers to a Music City Bowl appearance and a final record of 7–6 (4–4 in conference).

[53] On January 24, 2023, ESPN reported that Tennessee had reached a contract extension agreement that will keep Heupel in Knoxville until 2029, with an annual salary of $9 million.